The authors have administered physostigmine intravenously to three hospitalized manic patients on a double-blind basis. All three individuals showed clinical change both during and after the physostigmine period, which can be clearly delineated into three distinct phases. The behavioral modifications occurring during the physostigmine run did not qualitatively alter the underlying mania. The authors focus on ‘rebound’ phenomena, or post-physostigmine changes, as a possible clinical index with which chemically to characterize the initial state of amine imbalance responsible for a given affective illness. The data are considered consistent with an adrenergic-dopaminergic-cholinergic balance hypothesis of affective disorders, and may provide a relevant link in understanding the interface or crossover between manic and schizo-affective illness.